DESCRIPTION (provided by applicant): The frequent inability of in vitro assays and animal models to accurately predict human response to a new drug candidate results in costly drug development failures. HemoShear has developed a platform technology for biodiscovery and drug pharmacology screening that replicates human biological function in healthy and diseased organ systems by applying human-derived hemodynamic shear stress forces to primary human cells in co-culture. Our initial system replicates the human vascular system and enables the creation of disease conditions including vascular inflammation, early atherogenesis and diabetic complications. Our novel technology is being deployed for customers to investigate the cellular and molecular mechanisms of human vascular inflammation and the identification of novel biomarkers and transcriptional pathways for development of drug therapies. Completed Phase I: The objective of our completed Phase I proposal was to develop a more advanced pro-inflammatory systemthat profiles the human vascular response (EC/SMC) to oxidized low density lipoprotein (oxLDL), which has a widely recognized role in vascular inflammation and atherosclerosis. We are already using the Phase I advanced inflammatory system for functional assays, target validation and knock-down experiments for our customers. The Problem: There does not exist an in vitro human vascular pharmacology system that can guide pharma and biotech in making key go-/no-go decisions in drug discovery and development. Furthermore, the FDA now requires that vascular risk must be more thoroughly addressed during drug development, especially for Type 2 anti-diabetic therapies, and the need for a predictive vascular pharmacology system has been confirmed by pharma industryexecutives and customers (see Letters of Support). Proposed Phase II: The purpose of this Phase II SBIR proposal is to develop a predictive vascular pharmacology system for late-stage drug discovery and preclinical drug development. The HemoShear vascularsystem, developed in Phase I above, will be used to evaluate known drug compounds across a broad range of drug classes that have the following effects on the vasculature: 1) direct/intended effect (e.g. Ca channel blockers), 2) positive pleiotropic effect(e.g. statins) and 3) negative pleiotropic effect (e.g. rosiglitazone, Vioxx), in order to create a robust database of drug-related vascular effect profiles. We will use proprietary bioinformatics methods to develop a vascular signature predictor panel (~30 genes) from whole genome data sets that can be used for screening and scoring candidate compounds for vascular pharmacology response and potential safety risk. Value: Success of this Phase II SBIR will provide a predictive set of tools with which to assess human vascular response of customers' novel drug compounds, prior to human studies. PUBLIC HEALTH RELEVANCE: Over 90% of drugs that enter Phase I clinical trials ultimately fail because of lack of efficacy or adverse effects. It is estimated that65bln is spent annually in discovery, pre-clinical and clinical drug development. Much of that expenditure is wasted on failure, largely because of the inability of in vitro assays and animal models to accurately predict human response to a new drug candidate. HemoShear has developed a platform technology for biodiscovery and drug screening that replicates human biological function in healthy and diseased organ systems by applying human-derived hemodynamic shear stress forces to primary human cells in co-culture. HemoShear's patented system has been shown to validate efficacy, safety and off-target effects of known, FDA-approved drug compounds. The purpose of this Phase II SBIR proposal is to develop a predictive vascular pharmacology system to assess newdrug compounds in late-stage drug discovery and preclinical drug development.